# Antisense Oligonucleotides for Targeting Nonsense-mediated mRNA Decay in Frontotemporal Dementia

> **NIH NIH R01** · SAINT LOUIS UNIVERSITY · 2021 · $378,750

## Abstract

Project Summary
Progranulin is a lysosomal and secreted protein that contains multiple cysteine-rich granulin domains; its
precise molecular function remains unknown. Progranulin (GRN) mutations are causal for frontotemporal
dementia (FTD), which is a devastating disease with a mean survival of 3.8 years from diagnosis and no cure
currently available. Since progranulin-deficient FTD is a disease of haploinsufficiency, strategies aimed at
increasing progranulin levels are feasible therapeutic approaches. We recently generated a knock-in mouse
model of FTD harboring the common patient nonsense mutation GRNR493X, and we established that the
nonsense-mediated mRNA decay (NMD) pathway contributes to the markedly reduced mutant progranulin
mRNA levels in this mouse model, as wel`l as in patient-derived fibroblasts containing the GRNR493X mutation.
Moreover, our cell-based studies indicate that the progranulin R493X mutant protein is functional when re-
expressed in progranulin-deficient cells. Based on these results, we hypothesize that inhibiting NMD-mediated
degradation of the mutant GrnR493X mRNA would increase functional progranulin levels and thereby improve
FTD-associated behavioral changes and neuropathology. We will test this hypothesis in the following two
specific aims: Aim 1) Test in vivo efficacy of ASOs that block NMD-mediated degradation in the GrnR493X
knock-in mouse model of FTD, and Aim 2) Design and test ASOs that target NMD-mediated degradation of the
human GRNR493X mRNA. Completion of these studies will generate important preclinical data that provide
insights into the utility of ASO-based NMD inhibition as a therapeutic approach for progranulin-deficient FTD.

## Key facts

- **NIH application ID:** 10153636
- **Project number:** 5R01AG064069-03
- **Recipient organization:** SAINT LOUIS UNIVERSITY
- **Principal Investigator:** Andrew D. Nguyen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,750
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153636

## Citation

> US National Institutes of Health, RePORTER application 10153636, Antisense Oligonucleotides for Targeting Nonsense-mediated mRNA Decay in Frontotemporal Dementia (5R01AG064069-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153636. Licensed CC0.

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